Modern drug discovery techniques (e.g. combinatorial chemistry, high-throughput pharmacological screening, structure-based drug design) are providing very specific and potent drug molecules. However, it is rather common that these novel chemical structures have unfavorable physicochemical and biopharmaceutical properties. Besides, during the development of new therapeutic agents, researchers typically focus on pharmacological and/or biological properties, with less concern for physicochemical properties. However, the physicochemical properties (dissociation constant, solubility, partition coefficient, stability) of a drug molecule have a significant effect on its pharmaceutical and biopharmaceutical behavior. Thus, the physicochemical properties need to be determined and modified, if needed, during drug development. Moreover, the physicochemical properties of many existing drug molecules already on the market are not optimal.
Today, drug candidates are often discontinued due to issues of poor water solubility or inadequate absorption, leaving countless medical advances unrealized. Still other products make it to the market, but never realize their full commercial potential due to safety or efficacy concerns. Prodrugs have the potential to overcome both challenges. The technology exploits endogenous enzymes for selective bioconversion of the prodrug to the active form of the drug. This technology has the ability to keep promising new drug candidates alive through development, and improving the safety and efficacy of existing drug products.
Prodrugs are mostly inactive derivatives of a drug molecule that require a chemical or enzymatic biotransformation in order to release the active parent drug in the body. Prodrugs are designed to overcome an undesirable property of a drug. As such this technology can be applied to improve the physicochemical, biopharmaceutical and/or pharmacokinetical properties of various drugs. Usually, the prodrug as such is biologically inactive. Therefore, prodrugs need to be efficiently converted to the parent drugs to reach pronounced efficacy as soon as the drug target has been reached.
In general, prodrugs are designed to improve the penetration of a drug across biological membranes in order to obtain improved drug absorption, to prolong duration of action of a drug (slow release of the parent drug from a prodrug, decreased first-pass metabolism of the drug), to target the drug action (e.g. brain or tumor targeting), to improve aqueous solubility and stability of a drug (i. v. preparations, eyedrops, etc.), to improve topical drug delivery (e.g. dermal and ocular drug delivery), to improve the chemical/enzymatic stability of a drug (e.g. peptides) or to decrease drug side-effects.
Many prodrug technologies have already been developed depending on the kind of drug that has to be converted. These prodrug technologies include cyclic prodrug chemistry for peptides and peptidomimetics, phosphonooxymethyl (POM) chemistry for the solubilization of tertiary amines, phenols and hindered alcohols and esterification in general. Also targeting strategies are pursued by coupling groups cleavable by specific enzymes such as the peptide deformylase of bacteria which cleaves N-terminal formyl groups of the peptides or PSA (prostate specific antigen) used to target prostate cancer.
Coupling of peptides or amino acids to a therapeutic agent has already been pursued in the past for several reasons. In the antisense-antigene field, oligonucleotides or intercalators have been conjugated to peptides in order to increase the cellular uptake of the therapeutic agents. These oligonucleotides and intercalators have not to be released after cell penetration however, and can not be regarded as prodrugs. An example of amino acid coupling to a therapeutic compound is Valgancyclovir, the L-valyl ester prodrug of gancyclovir, which is used for the prevention and treatment of cytomegalovirus infections. After oral administration, the prodrug is rapidly converted to gancyclovir by intestinal and hepatic esterases. Recently, alanine and iysine prodrugs of novel antitumor benzothiazoles have been investigated [Hutchinson et al. (2002) J. Med. Chem. 45, 744-474].
Peptide carrier-mediated membrane transport of amino acid ester prodrugs of nucleoside analogues has already been demonstrated [Han et al. Pharm. Res. (1998) 15: 1154-1159; Han et al Pharm. Res. (1998) 15: 1382-1386]. It has indeed been shown that oral bioavailability of drugs can be mediated by amino acid prodrug derivatives containing an amino acid, preferably in the L-configuration. L-Valine seems to have the optimal combination of chain length and branching at the β-carbon of the amino acid for intestinal absorption. hPEPT-1 has been found to be implicated as the primary absorption pathway of increased systemic delivery of L-valine ester prodrugs. Recently, it was shown that the hPEPT-1 transporter need to optimally interact with a free NH2, a carbonyl group and a lipophilic entity, and may form a few additional H-bridges with its target molecule. L-Valine-linked nucleoside analogue esters may fulfill these requirements for efficient hPEPT-1 substrate activity [Friedrichsen et al. Eur. J. Pharm. Sci. (2002) 16: 1-13]. The prior art for ameliorating solubility and bioavailability reveals however only amino acid prodrugs (only one amino acid coupled) of small organic molecules whereby the amino acid is mostly coupled through ester bonds, since they are easily converted back to the free therapeutic agent by esterases.
Prior art documents describe processing of prodrugs by a number of proteases, such as aminopeptidases (PCT application WO01/68145) and aminotripeptidase (PCT application WO02/00263).
There is however still a need for new, alternative and better prodrug technologies and this need is projected to grow, as combinatorial chemistry and high throughput screening continue to produce vast numbers of new compounds with a high molecular weight, high log P [partition coefficient], or poor water solubility.